Iontophoresis electrode

ABSTRACT

An iontophoresis electrode that includes a reservoir for holding electrolytic solution, a pH buffer, the pH buffer immobilized within the reservoir and the pH buffer having a buffering capacity of at least about 0.5 milliequivalents of acid or base per gram of pH buffer, and an electrical connection in electrical communication with the reservoir.

BACKGROUND OF THE INVENTION

The present invention generally relates to an apparatus and a method fortransdermally delivering medicament ions derived from ionic substances,such as drugs or other therapeutic chemicals. More particularly, thepresent invention relates to an apparatus and a method ofiontophoretically introducing medicament ions into a body.

Iontophoresis may be generally described as a method of transdermallyintroducing medicament ions into a body. The iontophoresis processutilizes current developed by an electric field to drive medicament ionsthrough the skin, or other surface, and into the body. The iontophoresisprocess has been found to be particularly useful in transdermaladministration of medicament ions, such as charged organic medicationsand therapeutic metal ions.

Iontophoresis permits introduction of medicament ions directly into apatient's tissues and blood stream without the need for a needle-basedinjection, which typically causes pain and may create a risk ofinfection. Iontophoretic delivery of medicament ions also avoidspremature metabolism of medicament ions that typically occurs when drugsare taken orally. Premature metabolism is of concern because medicamentions derived from drugs that are taken orally are absorbed into theblood stream from the digestive system. The blood containing themedicament ions then percolates through the liver, where the medicamentions may be prematurely metabolized, before the medicament ions arriveat the target tissue. Thus, a substantial amount of the medicament ionsderived from an orally administered drug may be metabolicallyinactivated before the medicament ions have a chance topharmacologically act in the body.

A typical iontophoresis device includes two electrodes. One of theelectrodes is often characterized as an "active" electrode and the otherelectrode is often characterized as a "ground" electrode. Also, one ofthe electrodes is a positively charged anode and the other electrode isa negatively charged cathode. Both electrodes are in intimate electricalcontact with the skin or other surface of the body, which may be a humanbody or another type of body, such as an animal body. Application ofelectric current to the active electrode drives the medicament ion, suchas the charged organic medication, from the active electrode into thebody. The other electrode, the ground electrode, closes the electricalcircuit and permits current flow through the active electrode andthrough the body.

In some cases, medicament ions may be delivered to the body from bothelectrodes of the iontophoresis system. In such cases, a first electrodeis the active electrode for a first medicament ion that is deliveredfrom the first electrode, and a second electrode is the ground electrodewith respect to the first medicament ion. Similarly, the secondelectrode is the active electrode for a second medicament ion that isdelivered from the second electrode and the first electrode is theground electrode with respect to the second medicament ion. Typically,the first and second medicament ions are different in polarity and inchemical structure from each other.

A variety of patents discuss iontophoresis systems, iontophoresiselectrodes, and/or methods of iontophoretically administering medicamentions. Examples of these patents include U.S. Pat. Nos. 4,744,787 toPhipps et al.; 4,752,285 to Petelenz et al.; 4,820,263 to Spevak et al.;4,886,489 to Jacobsen et al.; 4,973,303 to Johnson et al.; and 5,125,894to Phipps et al.

Some patents provide details about the reservoirs of electrodes. Forexample, U.S. Pat. No. 4,702,732 to Powers et al. describes thereservoir in terms of a polymer matrix. The Powers patent comments that,when the polymeric matrix is hydroxyethyl methacrylate, a hydrogel, thepharmacologically active ligand may be added to the hydrogel reactionmixture prior to polymerization or may be introduced into the hydrogelmatrix after formation of the matrix. U.S. Pat. No. 5,302,172 to Sage,Jr. et al. comments that the reservoir containing the active agent to bedelivered may be made of a variety of materials, including foams,ion-exchange resins, gels, matrices. Also, U.S. Pat. No. 5,328,455 toLloyd et al. describes a multi-layer hydrogel reservoir of aniontophoretic electrode that may incorporate ion-exchange resin

Other references describe incorporation of ion-exchange substances intodevices other than buffered electrodes. For example, Braun, AnaltlicaBased Chimica Acta, Vol. 64, pp. 45-54 (1973), comments upon preparationof ion-exchange foams for use in ion-exchange foam chromatography. TheBraun reference mentions preparation of homogeneous ion-exchange foamsby introduction of ion-exchange groups onto a previously preparedplastic foam, such as by surface or penetrating treatment. The Braunreference also discusses preparation of heterogeneous ion-exchange foamsby foaming a cation exchange material, in powder form, with precursorsof an open cell polyurethane foam. Also, Australian Pat. No. 629,790describes an electrode that is used in wastewater treatment and waterdesalinization processes for recovering metals. The electrodeincorporates a polyurethane foam that includes ion-exchange resin.

Though iontophoresis system technology has realized several advances,numerous problems remain to be solved and many opportunities forenhancing performance remain. Examples of some suggested changes forfuirther optimizing iontophoresis systems are included in U.S. Pat. Nos.4,731,049 to Parsi; 4,915,685 to Petelenz et al.; and 5,302,172 to Sage,Jr. et al. For example, the Parsi patent suggests a change in theiontophoresis system that is said to increase the types of drugsdeliverable by iontophoresis systems. Also, the Petelenz patent suggestschanges that are said to enhance the proportional relationship betweenthe amount of medicament administered and current flow. Finally, theSage, Jr. patent discloses the use of vasodilators in iontophoresis as ameans of enhancing delivery of an active agent that is delivered alongwith the vasodilator.

Despite the many advances in iontophoresis technology, a series ofproblems remain that relate to electrolysis of water in iontophoresissystem electrodes. As an example, current passing through the electrodesof an iontophoresis system typically causes electrolysis of water. Inthe anode, the electrolysis reaction proceeds as follows:

    2H.sub.2 O→O.sub.2 +4H.sup.+ 4.sub.e.sup.-

In the cathode, the electrolysis reaction proceeds as follows:

    2H.sub.2 O+2.sub.e.sup.- →H.sub.2 +2OH.sup.-

Since an operational iontophoresis system includes both an anode and acathode, both hydrogen ions (H⁺) and hydroxide ions (OH⁻) are producedduring system operation. Absent buffering, the hydrogen ionconcentration will increase at the anode and the hydroxide ionconcentration will increase at the cathode.

The hydrogen ion and hydroxide ion accumulation in the electrodes ofiontophoresis systems is problematic for a variety of reasons. Forexample, the increased hydrogen ion concentration shifts the pH downwardat the anode, and the increased hydroxide ion concentration shifts thepH upward at the cathode. The pH shift typically causes at least minorskin irritation and can cause severe burning of a patient's skin. Also,the pH shift can change the activity of the medicament ion(s) beingdelivered by the electrode and can even degrade the physical propertiesof the electrode components.

A variety of changes in the operation and structure of iontophoresissystems have been suggested to control or minimize the pH shift causedby electrolysis of water. For example, U.S. Pat. No. 4,886,489 toJacobsen et al. discloses a flow-through electrode in which hydrogenions or hydroxide ions produced during iontophoresis are constantlyremoved. As a result of the flushing, the Jacobsen patent alleges thatthe pH within the iontophoresis system can be maintained within desiredlevels without addition of buffers. However, though the Jacobsenflushing system may help to maintain desirable pH levels, addition ofthe flushing mechanism unnecessary complicates the iontophoresis system.Also, the flushing mechanism removes desirable, and sometimes expensive,medicament ions. Additionally, the flushing mechanism is a dynamicsolution as opposed to a more desirable static solution to the pH shiftproblem, such as an improved buffering system.

The Petelenz patent, U.S. Pat. No. 4,752,285, discloses an iontophoresissystem that includes a reactive electrode and control of voltage in thesystem. The Petelenz '285 patent mentions a silver electrode and a leadelectrode as examples of the reactive electrode. According to thePetelenz '285 patent, use of the reactive electrode permitsiontophoresis to occur, at select medicament and complimentary ionconcentrations and at select voltage, without electrolysis of water andconsequent pH shift. However, the present inventor has found that thesecomments of the Petelenz '285 patent about the absence of waterelectrolysis and pH shift are inaccurate.

Specifically, the present inventor has determined that metal oxidestypically form on the reactive metal electrode prior to use of thereactive metal electrode in accordance with the Petelenz '285 patent.The metal oxides of the reactive metal electrode, such as silver oxidethat forms on the reactive silver electrode, support electrolysis ofwater in the iontophoresis system. The electrolysis of water that occurscreates localized pH shifts of sufficient magnitude to cause localizedirritation of patient's skin during iontophoretic use of the Petelenz'285 electrode. Another concern is that the Petelenz '285 system is saidto control the pH shift without addition of buffering ions. However,this solution to the pH shift problem introduces a precipitate. Thoughthe precipitate is said to be practically insoluble in the transportmedium, any precipitate that does solubilize will compete with themedicament ion for delivery to the body.

Another technique for controlling the pH shift involves introduction ofone or more buffering species into the iontophoretic electrodes. Thebuffering species may be in solution with the medicament ion to bedelivered. However, when the buffering species is in solution with themedicament ion, experience has shown that the buffer species andderivatives of the buffer species remain mobile within the electrode andundesirably compete with medicament ions for delivery to the body.Alternatively, the buffering species may be immobilized within theiontophoresis electrode, as disclosed in U.S. Pat. No. 4,973,303 toJohnson et al. The buffered electrode disclosed in the Johnson patentsignificantly reduces the problem associated with mobile bufferingspecies. However, it has been found that the amount of ion-exchangefunctionality included in the buffer of the Johnson buffered electrodecan not be accurately controlled.

Though many advances in iontophoretic electrode design and operationhave been realized, challenges requiring solution remain. For example,less complicated and more accurate techniques are needed for controllingthe amount of ion-exchange functionality included on immobilizedbuffers. Also, opportunities remain for simplifying the structure andthe manufacture of iontophoresis electrodes. Finally, opportunitiesremain for further reducing competing ion concentrations iniontophoresis systems.

SUMMARY OF THE INVENTION

The present invention includes a pH buffered electrode with a reservoirfor holding electrolytic solution, a pH buffer that is immobilizedwithin the reservoir and an electrical connection in electricalcommunication with the reservoir. The pH buffer has a buffering capacityof at least about 0.5 milliequivalents of acid or base per gram of pHbuffer. The present invention further includes an iontophoresiselectrode, a method of making an iontophoresis electrode, and a methodof making a pH buffered electrode.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of a pH buffered electrode of the presentinvention.

FIG. 2 is a sectional view of another pH buffered electrode of thepresent invention.

FIG. 3 is a sectional view of another pH buffered electrode of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An iontophoresis electrode of the present invention is generallydepicted at 10 in FIG. 1. The electrode 10 includes a reservoir 12 thatcontains an electrolytic solution of medicament ions and complimentaryions of the medicament ions. The electrode 10 also includes a conductivelayer 14 that is located adjacent to the reservoir 12. The electrode 10further includes a conductive terminal 16 that is attached to theconductive layer 14. The terminal 16 couples the electrode 10 to asource of electrical power (not shown), such as a source of directcurrent. The electrode 10 also includes a wicking wrap 18 that holds thereservoir 12 and the conductive layer 14 together. An adhesive covering20 may also be attached to the conductive layer 14 opposite thereservoir 12 to aid in adhering the electrode 10 to a surface (notshown), such as the skin of a human or animal body.

Any substance that is to be iontophoretically delivered to the bodyexists as medicament ions. The electrolytic solution that is included inthe electrode 10 may include one or more different types of medicamentions. Charged organic medications and therapeutic metal ions areexamples of medicament ions. It will be appreciated that transportationof medicament ions through the skin of the human or animal body takesplace in an electrical field such as that produced in an iontophoresissystem that includes two electrodes, as well as, a source of electricalcurrent.

The medicament ions that are present in the electrolytic solution may bederived from any suitable ionic substance. The ionic substance may beany suitable salt, acid, or base that dissociates into medicament ions,and complimentary ions of the medicament ions, in the electrolyticsolution. Medications, drugs, and other therapeutic chemicals are somegeneral examples of suitable ionic substances. Some examples ofparticular ionic substances that may evolve medicament ions in theelectrolytic solution include morphine sulfate, dexamethasone sodiumphosphate, hydrocortisone derivatives, magnesium chloride, lidocainehydrochloride, morphine hydrochloride, steroids, penicillin, aceticacid, fluoride, nitroglycerine, enzymes, vitamins, antibodies, hormones,and a variety of anesthetics.

Though the electrolytic solution of some iontophoresis system electrodemay not include medicament ions, these iontophoresis system electrodesshould nevertheless include suitable conductive ions. The conductiveions are needed to support current flow through the iontophoresissystem. The conductive ions should be selected so that any conductiveions that are delivered into the body during iontophoresis do not causedeleterious effects within the body. The solvent of the electrolyticsolution that is included in any electrode of the iontophoresis systemmay be any solvent, such as water, that suitably solubilizes medicamentions or conductive ions that are included in the electrolytic solution.Additionally, the solvent of the electrolytic solution should selectedto avoid any harmful effects to the body.

Medicament ions formed on dissociation of ionic substances are desirableions that are intended for delivery into the human or animal body.Complimentary ions formed on dissociation of ionic substances are ionsthat are not intended for delivery into the human or animal body. Asidefrom complimentary ions, other ions that are not intended for deliveryinto the human or animal body are subsequently referred to as adverseions.

An iontophoresis system (not shown) typically includes two electrodes(not shown) that are in electrical contact with the body. Either or bothof the electrodes of the iontophoresis system may have the structure ofthe electrode 10. One of the electrodes of the iontophoresis system maybe characterized as an "active" electrode of the system, and the otherelectrode may be characterized as a "ground" electrode of the system.One of the electrodes of the iontophoresis system also serves as apositively charged anode and the other electrode is a negatively chargedcathode. When one of the electrodes delivers medicament ions to thebody, the electrode delivering the medicament ions is the activeelectrode and the other electrode, the ground electrode, completes theelectrical circuit through the body between the active electrode and theground electrode.

When the anode of the iontophoresis system has the structure of theelectrode 10, electrolytic solution is included in the reservoir 12 tosupport current flow from the terminal 16 through conductive layer 14and the reservoir 12 and into the body. The electrode 10 that serves asthe anode may be either the active electrode for delivering medicamentions into the body or may be the ground electrode. When the cathode ofthe iontophoresis system has the structure of the electrode 10,electrolytic solution is included in the reservoir 12 to support currentflow from the body through the reservoir 12 and the conductive layer 14and into the terminal 16. The electrode 10 that serves as the cathodemay be either the active electrode for delivering medicament ions intothe body or may be the ground electrode. Additionally, as explainedbelow, the anode and the cathode that have the structure of theelectrode 10 may each serve as both active and ground electrodes whenmedicament ions are delivered from both the anode and the cathode.

The reservoir 12 consists of a structural matrix that accepts and holdsthe electrolytic solution of any dissociated ionic substance(s). Theelectrolytic solution may be introduced into the matrix of the reservoir12 by a conventional technique, such as by injection with a hypodermicneedle. The reservoir 12 may hold the electrolytic solution ofmedicament ions and complimentary ions both prior to and during use ofthe electrode to deliver medicament ions into the body. In the electrode10 of FIG. 1, the wicking layer 18 may also contain the electrolyticsolution.

The reservoir 12 and the wicking layer 18 should be sized to ensure thatsubstantially all of the electrolyte solution is held within thereservoir 12 to enhance contact between the pH buffer and theelectrolyte solution. At least about 75% of the volume of theelectrolytic solution should be held within the reservoir 12.Preferably, at least about 90% of the volume of the electrolyticsolution is held in the reservoir 12. In one embodiment of the electrode10, about 2 milliliters of the electrolytic solution are contained inthe combined volume of the reservoir 12 and the wicking layer 18.Together, the reservoir 12 and the wicking layer 18 should contain atleast enough medicament ions for one session of patient treatment.

The reservoir 12 of the electrode 10, in addition to holding theelectrolytic solution of medicament ions, may also incorporate a pHbuffer that is immobilized within the reservoir 12. The pH bufferneutralizes hydrogen ions or hydroxide ions generated by electrolysis ofwater when current is applied to the iontophoresis system. Hydrogen ionsand hydroxide ions are examples of adverse ions that are not intendedfor delivery into the human or animal body. Additionally, bufferingions, and complimentary ions of the buffering ions, that are formed ondissociation of the pH buffer in the electrolytic solution are examplesof adverse ions that are not intended for delivery into the human oranimal body.

When the iontophoresis system is buffered to neutralize hydrogen orhydroxide ions generated by electrolysis of water, the pH buffer of thereservoir 12 preferably neutralizes any hydrogen ions or hydroxide ionsthat are generated in the electrode 10. If the anode of theiontophoresis system is structured like the electrode 10, basic elementsincluded in the reservoir 12 neutralize hydrogen ions generated at theanode. If the cathode of the iontophoresis system is structured like theelectrode 10, acidic elements included in the reservoir 12 neutralizehydroxide ions generated at the cathode.

One significant benefit of the present invention is the ability toclosely and accurately control the dosage of pH buffer that is includedin the electrode 10. For example, the method of the present inventionpermits a predetermined amount of pH buffer material to be measured andfully incorporated into the structural matrix of the reservoir 12.Existing techniques, such as dipping an electrolyte containment matrixin an aqueous suspension of pH buffer, do not permit adequate control ofthe quantity of buffer that is associated with the matrix sincevariables controlling how much buffer sticks to the matrix may changewith time. Also, buffer that adheres less strongly to the matrix may beeasily abraded or otherwise separated from the matrix. Thus, in order tomake electrodes that adequately maintain a safe pH range proximate theskin, it is typically necessary to apply as much as ten times more pHbuffer material to existing electrodes than is chemically necessary forthe actual neutralization of hydrogen or hydroxide ions.

Another significant benefit of the electrode 10 is that the pH buffermaterial is immobilized within the structure of the reservoir 12 whichprevents losses of pH buffer material from the reservoir 12 duringassembly and handling. Immobilization of the pH buffer within thereservoir 12 also prevents losses of buffer ions from the reservoir 12during use of the electrode 10. In existing iontophoresis systems, pHbuffer material that is not secured within the storage matrix may beabraded from or otherwise be separated away from the electrode. This isnot a problem with the inventive electrode 10 since the pH buffermaterial is integrally incorporated within the structure of thereservoir 12. The pH buffer material may even be chemically bonded inplace within the reservoir 12. Integral incorporation of pH buffermaterial prevents movement of pH buffer material within the reservoir12, or away from the reservoir 12, with the result that the pH buffermaterial remains uniformly dispersed within the reservoir 12 during useof the electrode 10 in iontophoresis. Uniform dispersal of the pH buffermaterial in the reservoir 12 helps maintain uniform pH levels along theinterface of the electrode 10 and the skin during use of the electrode10.

Though the reservoir 12 of the electrode 10 may be multi-layered, thereservoir 12 preferably consists of only a single, monolithic layer.Formation of the reservoir 12 as a single layer simplifies the structureand manufacture of the reservoir 12, while maintaining performancebenefits of the reservoir 12. The layer, or layers, of the reservoir 12may generally be made of any permeable material that has suitableabsorbent characteristics. Some examples of the permeable materialinclude foamed materials, such as polyurethane foam; woven or knittedfibers and fabrics, such as felt and polyester fleece; and non-wovenfabrics.

Permeable materials that are used as the layer(s) of the reservoir 12should be highly absorbent, should have a relatively large specificabsorbency, and should absorb the electrolytic solution at a relativelyhigh rate. High absorbency is needed so that the surface area and weightof the reservoir 12 and the dimensions and weight of the electrode 10can be minimized without sacrificing the quantity of medicament ionsthat the electrode 10 is capable of administering. The permeablematerial needs to have a relatively high rate of absorption so that theelectrolytic solution can be quickly placed in the reservoir 12. Therelatively high rate of absorption also minimizes or eliminates lossesof the electrolytic solution from the electrode 10 during incorporationof the electrolytic solution into the reservoir.

The permeable material should be capable of absorbing at least about 600milliliters of electrolytic solution per square meter of permeablematerial surface area. Preferably, the permeable material should becapable of absorbing at least about 1000 milliliters of electrolyticsolution per square meter of permeable material surface area. Morepreferably, the permeable material should be capable of absorbing atleast about 2000 milliliters of electrolytic solution per square meterof permeable material surface area.

For purposes of determining absorbency, the surface area of thepermeable material is determined after the permeable material has beenformed into the layer(s) of the reservoir 12. Each layer will have majorsurfaces and minor surfaces. Since the thickness dimension of each layerwill typically be orders of magnitude less than the length and widthdimensions, the diameter dimension, or other dimension of the layer, theminor surfaces are defined as those surfaces that encompass thethickness of the layer, and the major surfaces are defined as thosesurfaces that do not encompass the thickness of the layer. Where thereservoir 12 includes multiple layers of the permeable material, each ofthe layers should have essentially the same major surface dimensions sothat each layer is essentially coextensive with the other layers. Thoughthe layers do not necessarily need to have the same thickness, thelayers preferably do have substantially the same thickness. Theabsorbency of the permeable material may be determined by applying theelectrolytic solution to any major surface of any layer of permeablematerial. The surface area of the permeable material, for purposes ofevaluating absorbency, is the surface area of the major surface to whichthe electrolytic solution is applied.

Also, the permeable material should have a relatively high specificabsorbency of at least about 0.5 milliliters of electrolytic solutionper gram of permeable material. Preferably, specific absorbency of thepermeable material should be at least about 1.0 milliliters ofelectrolytic solution per gram of permeable material. More preferably,the specific absorbency of the permeable material should be at leastabout 3.0 milliliters of electrolytic solution per gram of permeablematerial.

Furthermore, about 3 milliliters of the electrolytic solution should beabsorbed into 1 gram of the permeable material in less than about 3minutes. Preferably, about 3 milliliters of the electrolytic solutionshould be absorbed into 1 gram of the permeable material in less thanabout 1 minute. More preferably, about 3 milliliters of the electrolyticsolution should be absorbed into I gram of the permeable material inless than about 10 seconds.

The permeable material may generally be or incorporate any pH buffermaterial in any form. For example, the permeable material may be orincorporate ion-exchange material, such as ion-exchange material that isorganic in chemical structure, Thus, the permeable material may be orincorporate anionic or cationic ion-exchange material. Additionally, thepermeable material may incorporate or consist of anionic and cationicion-exchange materials or amphoteric ion-exchange material. This permitsinterchangeable use of the electrode 10 as the anode or the cathode ofthe iontophoresis system or, alternatively, as the anode and the cathodeof the iontophoresis system.

The pH buffer material, such as the ion-exchange material should becapable of maintaining the pH of the electrolytic solution within arange of from about 4 to about 8 to avoid irritating or burning theskin. For example, the pH buffer material should be capable of holdingabout 0.1 milliequivalents of acid or about 0.1 milliequivalents of basewhile maintaining the about 4 to about 8 pH range of the electrolyticsolution. Preferably, the pH buffer material is capable of holding about0.1 milliequivalents of acid and about 0.1 milliequivalents of basewhile maintaining the about 4 to about 8 pH range of the electrolyticsolution.

The pH buffer material should also have a relatively high bufferingcapacity to aid in minimizing the size and weight of the reservoir 12while maintaining the about 4 to about 8 pH range of the electrolyticsolution during iontophoresis periods on the order of about 40 minutesor more. At a minimum, the buffering capacity of the pH buffer materialshould be at least about 0.5 milliequivalents of acid or base per gramof pH buffer material. Preferably, the buffering capacity of the pHbuffer material should be at least about 1.0 milliequivalents of acid orbase per gram of pH buffer material More preferably, the bufferingcapacity of the pH buffer material should be at least about 1.5milliequivalents of acid or base per gram of pH buffer material. Stillmore preferably, the buffering capacity of the pH buffer material shouldbe at least about 1.5 milliequivalents of acid per gram of pH buffermaterial and at least about 1.5 milliequivalents of base per gram of pHbuffer material.

The ion-exchange material may consist of ion-exchange functionalitiesthat are chemically bonded to the permeable material. Examples ofsuitable ion-exchange materials include any homogeneous ion-exchangematerial, such as ion-exchange polymer and ion-exchange copolymer. Inhomogeneous ion-exchange material, one or more different ion-exchangefunctionalities are chemically bonded to the homogeneous ion-exchangematerial.

One type of ion-exchange copolymer consists of the reaction product of afirst prepolymer and a second prepolymer. The first prepolymer maygenerally be any monomeric precursor or a mixture of different monomericprecursors. The second prepolymer may generally be any monomericionexchange precursor or a mixture of different monomeric ion-exchangeprecursors. Monomeric ion-exchange precursor may be formed by attachingone or more ion-exchange functional groups to any monomeric precursorsusing any conventional chemical bonding technique, such as substitutionor grafting. At least one of the monomeric precursors that acts as thefirst prepolymer and at least one of the monomeric precursors that isused in forming the monomeric ion-exchange precursor should be differentfrom each other. Another type of ion-exchange copolymer consists of agraft ion-exchange copolymer where one or more ion-exchangefunctionalities are chemically grafted or substituted onto a corecopolymer. One type of ion-exchange polymer consists of a graftion-exchange polymer where one or more ion-exchange functionalities arechemically grafted or substituted onto a core polymer.

Alternatively, the ion-exchange material may be physically entrappedwithin the permeable material. The molecular weight of any ionexchangematerial that is physically entrapped in the permeable material shouldbe at least about 5000 daltons (grams per mole) to immobilize theion-exchange material in the permeable material. As an example, the ionexchange material may be any heterogeneous ion-exchange material, suchas heterogeneous ionexchange foam. Heterogeneous ion-exchange foamincludes at least two distinct phases. For any electrode that includesthe heterogeneous ion-exchange foam, each of the phases should beinsoluble in the solvent portion of any electrolytic solution includedin the electrode to immobilize physical movement of any component of theheterogeneous ion-exchange foam within the electrode. The phases mayeach be solid or semi-solid in nature. Alternatively, some phase(s) maybe solid in nature, and other phase(s) may be semi-solid in nature. Oneor more organic ion-exchange substances make up one or more of thephases, and polymer foam or copolymer foam makes up the other phase(s).

Heterogeneous ion-exchange foam is made by dispersing one or moreorganic ion-exchange substances in one or more prepolymer components ofpolymer or copolymer foam, prior to reacting the prepolymer componentsto make the polymer or copolymer foam. After formation of theheterogeneous ion-exchange foam, the polymer or copolymer foam and theorganic ionexchange substance(s) form the distinct phases of theheterogeneous ion-exchange foam. In the heterogeneous ion-exchange foam,the organic ion-exchange substance(s) are physically entrapped withinthe structure of the polymer or copolymer foam. Preferably, the polymeror copolymer foam portion of the heterogeneous ion-exchange foam is anopen cell foam that supports enhanced movement within the heterogeneousion-exchange foam of any medicament ion included in the electrolyticsolution.

Other examples of heterogeneous ion-exchange materials include variouscomposite polymer mixtures of host polymeric material and organicionexchange functionality. The host polymeric material may be formed asa gel, a membrane, a hydrocolloid, a membrane, a laminate, particles,granules, or other suitable matrix. The ion-exchange functionality maybe dispersed within the host polymeric material, such as by impregnatingthe ion-exchange functionality within the host polymeric material eitherbefore or after formation of the host polymeric material. In this form,the ion-exchange functionality is physically entrapped within the hostpolymeric material. The molecular weight of any ionexchange materialthat is incorporated in host polymeric material should be at least about5000 daltons (grams per mole) to immobilize the ion-exchange material inthe host polymeric material. The ion-exchange finctionality may also becoated onto the host polymeric material. WVhen the host polymer materialis a loose material, such as in the form of particles or granules, thereservoir 12 may include suitable boundary layers (not shown) forcontaining the host material within the reservoir 12.

Alternatively, the permeable material of the reservoir 12 may be or mayinclude a proton sponge. The proton sponge, which may serve as the pHbuffer, is essentially an effective base compound that exhibits weaknucleophilic character. Proton sponges exhibit weak nucleophiliccharacteristics due to steric effects that are present within the protonsponge. The steric effects influence ionic reactions of the protonsponge and contribute to the weak nucleophilic character. The weaknucleophilic character causes the proton sponge to exhibit minimalelectron donation tendencies.

Steric effects exist in proton sponges for a variety of reasons,including the spacing between adjacent groups that are attached to theproton sponge, and the shape of the proton sponge. Proton sponges,however structured, are referred to as "proton sponges" because of theextremely high affinity of the underlying structure for protons. In thisapplication, including the specification and the claims, proton spongeis to be understood as referring to any compound that is capable oftrapping protons without consequent release of any other ion(s),including, but not limited to compounds, that are characterized in thisapplication as proton sponges or analogues of proton sponges.

One benefit of the present invention is the ability to closely andaccurately control the dosage of proton sponge material, such as protonsponge functional groups, that is included in the electrode 10.Homogeneous incorporation of proton sponge functional groups into thelayer(s) of the reservoir 12, such as by chemical bonding, secures theproton sponge functional groups within the structural matrix of thereservoir 12 and prevents losses of proton sponge functional groups fromthe reservoir 12 during assembly, handling, and use of the electrode.When the proton sponge material is heterogeneously incorporated in thelayers of the reservoir 12, the molecular weight of the proton spongematerial should be at least about 5000 daltons (grams per mole) toimmobilize the proton sponge material in the reservoir 12.

Although the permeable material may be or may incorporate any suitableproton sponge, three particular types of proton sponges are illustrativeof proton sponges that may be incorporated in the permeable material. Afirst type of proton sponge, subsequently referred to as "Type A" protonsponge, may be characterized as an organic carrier compound thatincludes one or more attached proton sponge functional groups. Eachproton sponge functional group consists of a neighboring pair of protonsponge functional group components. In the Type A proton sponge, aninorganic component or atom, such as nitrogen, of each proton spongefunctional group component is attached to, but is not a part of, thecarrier compound. One example of the Type A proton sponge is1,8-Bis(diethylamino)-2,7-dimethoxynaphthalene, which has the followingstructure: ##STR1##

For 1,8-Bis(diethylamino)-2,7-dimethoxynaphthalene, the carrier compoundis 2,7-dimethoxynaphthalene and the diethylamino groups are the protonsponge functional group components. Together, the two diethylaminogroups form the proton sponge functional group. In the Type A protonsponge, close spacing of the neighboring proton sponge functional groupcomponents hinders movement of reactants toward the proton sponge.Taking 1,8-Bis(diethylamino)-2,7-dimethoxynaphthalene as an example, theclose spacing of the two diethylamino groups forces the lone pair ofnitrogens near each other and creates steric strain in the protonsponge. Protonation of sterically strained proton sponges, such asaddition of hydrogen ion between adjacent strained nitrogens, relievesthe strain between the nitrogens, stabilizes the Type A proton sponges,and enables further ionic reaction of the protonated Type A protonsponges.

For example, in 1,8-Bis(diethylamino)-2,7-dimethoxynaphthalene, resonantcovalent bonding of hydrogen to the nitrogens of the respective protonsponge functional group components, along with resonant hydrogen bondingbetween hydrogen and the nitrogens of the respective proton spongefunctional group components, relieves the strain between the lone pairof nitrogens and stabilizes the proton sponge. At any particular pointin time, the hydrogen may be covalently bonded to the nitrogen of one ofthe proton sponge functional group components and may form a hydrogenbond with the nitrogen of the other proton sponge functional groupcomponent. Due to the resonant nature of the covalent bonding and thehydrogen bonding, at a different point in time, a hydrogen bond mayexist where a covalent bond formerly existed between the hydrogen andthe nitrogen of the one of the proton sponge functional groupcomponents, and a covalent bond may exist where a hydrogen bond formerlyexisted between the hydrogen and the nitrogen of the other proton spongefunctional group component.

A second type of proton sponge, subsequently referred to as a "Type B"proton sponge, may be characterized either as (1) a heterocycliccompound that includes at least one pair of hetero atoms or as (2) astraight or branched organic chain that includes at least one pair ofhetero atoms in the chain. Subsequent references to "organic corecompound" are to be understood as referring (1) to the heterocycliccompound, of the Type B proton sponge, that includes at least one pairof hetero atoms or as referring (2) to the straight or branched organicchain, of the Type B proton sponge, that includes at least one pair ofhetero atoms in the chain. In the Type B proton sponge, each of thehetero atoms is substituted in the organic core compound in place ofcarbon. One example of the Type B proton sponge is quino 7,8-h!quinoline, which has the following structure: ##STR2##

In quino 7,8-h!quinoline, nitrogen is substituted in place of carbon atone position in each of the two organic rings of the organic corecompound. In the Type B proton sponge, the shape of the organic corecompound places the pair of hetero atoms relatively close together andhinders movement of reactants toward the pair of hetero atoms. Takingquino 7,8-h! quinoline as an example, the shape of the organic corecompound places the pair of nitrogens near each other and hindersmovement of reactants toward the nitrogens. Protonation of Type B protonsponges, such as addition of hydrogen ion between adjacent hetero atoms,stabilizes the Type B proton sponges and enables further ionic reactionof the protonated Type B proton sponge. For example, in quino 7,8-h!quinoline, resonant covalent bonding of hydrogen to one of theheterocyclic nitrogen along with resonant hydrogen bonding betweenhydrogen and the other of the heterocyclic nitrogens stabilizes the TypeB proton sponge and enables further ionic reaction of the protonatedquino 7,8-h! quinoline. At any particular point in time, the hydrogenmay be covalently bonded to one of the heterocyclic nitrogens of theproton sponge and may form a hydrogen bond with the other heterocyclicnitrogen of the proton sponge. Due to the resonant nature of thecovalent bonding and the hydrogen bonding, at a different point in time,a hydrogen bond may exist where a covalent bond formerly existed betweenthe hydrogen and one of the heterocyclic nitrogens of the proton sponge,and a covalent bond may exist where a hydrogen bond formerly existedbetween the hydrogen and the other of the heterocyclic nitrogens of theproton sponge.

A third type of proton sponge, subsequently referred to as a "Type C"proton sponge, may be characterized as (1) a heterocyclic compound thatincludes at least one hetero atom or may be characterized as (2) astraight or branched organic chain that includes at least one heteroatom in the chain. Subsequent references to "organic support compound"are to be understood as referring to (1) the heterocyclic compound, ofthe Type C proton sponge, that includes at least one hetero atom or to(2) the straight or branched organic chain, of the Type C proton sponge,that includes at least one hetero atom in the chain. The hetero atom issubstituted into the organic support compound in place of carbon and atleast two organic groups are attached to carbons of the organic supportcompound that are located adjacent to the hetero atom. Also, in the TypeC proton sponge, one of the two organic groups is attached to a carbonthat is on one side of the hetero atom, and the other of the two organicgroups is attached to a carbon that is on the other side of the heteroatom. Thus, the two organic groups are attached to carbons that arelocated on opposing sides of the hetero atom. One example of the Type Cproton sponge is 2,6-di-t-butyl pyridine, which has the followingstructure: ##STR3## In 2,6-di-t-butylpyridine, nitrogen is substitutedin place of carbon at one position in the organic ring. Also, twot-butyl groups are attached to ring carbons located next to the ringnitrogen so that the t-butyl groups are located on opposing sides of thering nitrogen.

In the Type C proton sponge, the bulky nature of the organic groups thatare attached on opposing sides of the hetero atom hinders movement ofreactants toward the hetero atom. For example, in2,6-di-t-butylpyridine, the t-butyl groups attached on opposing sides ofthe ring nitrogen hinder movement of reactants toward the ring nitrogen.Protonation of Type C proton sponges, such as addition of hydrogen ionto the hetero atom, stabilizes the Type C proton sponges and enablesfurther ionic reaction of the protonated Type C proton sponge. Forexample, in 2,6-di-t-butyl pyridine, covalent bonding of hydrogen to thering nitrogen stabilizes the proton sponge and enables further ionicreaction of the protonated 2,6-di-t-butylpyridine.

It has been discovered that proton sponges are capable of acceptinghydrogen ions (H⁺) that are generated by electrolysis of water at theanode during iontophoretic delivery of medicament ions, such aslidocaine hydrochloride. More specifically, it has been found thatproton sponges, unlike ion-exchange compounds, are capable of scavenginghydrogen ions (H⁺) that are generated at the anode during iontophoreticdelivery of medicament ions, without releasing any ions. Ion-exchangecompounds, by definition, exchange ions and thus accept ions and releaseions during ion-exchange reactions. Proton sponges, by virtue of thisscavenging characteristic, are capable of acting as ion scavengers thataccept hydrogen ions without releasing any adverse ions that willcompete with medicament ions for delivery to the body. Besides lidocainehydrochloride, examples of other ionic substances that may beadvantageously administered at the anode in the presence of the protonsponge include papaverine hydrochloride, morphine hydrochloride,pilocarpine hydrochloride, ephedrine hydrochloride, lignocainehydrochloride, cetylpyridinium chloride, chloroprocaine hydrochloride,chlortetracycline hydrochloride, imipramine hydrochloride, etc.

As noted, permeable material may be used to make the layer(s) of thereservoir 12 that is depicted in FIG. 1. Any layer(s) of the permeablematerial may be or may incorporate homogeneous ion-exchange material orheterogeneous ion-exchange material. Alternatively, any layer(s) of thepermeable material may incorporate or may consist entirely of protonsponge. Furthermore, any layer(s) of the permeable material may includehomogeneous ion-exchange material, heterogeneous ion-exchange material,and/or proton sponge, in any combination and in any ratio.

Continuing with FIG. 1, the conductive layer 14 of the electrodeconducts current that is applied to the terminal 16 and distributes thecurrent across an inner surface 22 of the reservoir 12. The conductivelayer 14 should uniformly distribute current across the inner surface22. Preferably, the current density proximate the interface of theelectrode 10 and the skin does not exceed about 0.5 milliamperes persquare centimeter. Current densities proximate the skin of higher thanabout 0.5 milliamperes per square centimeter increase the likelihood ofpatient discomfort and irritation of the skin.

The conductive layer 14 may be formed of any suitable conductivematerial. Preferably, the conductive layer 14 is highly conductive andhas a maximum resistivity of about 10 olms cm to enhance the efficiencyof the electrode 10. The conductive layer 14 should also be flexible sothe electrode can closely conform to the shape of the skin. To preventdegradation of the electrochemical characteristics of the electrode 10,the conductive layer 14 should be impermeable to fluids, such as theelectrolytic solution contained in the electrode 10. Examples ofsuitable materials for the conductive layer include thin sheets ofcarbon-loaded silicon rubber, metal foil, conductive cloth, orconductive adhesive.

The wrap 18 of the electrode 10 aids in holding the reservoir 12 and theconductive layer 14 together. When the electrode 10 is placed againstthe skin, the wrap 18 is in contact with the body and separates thereservoir 12 from the body. One use of the electrode 10 is to transfermedicament ions derived from ionic substances, such as medications,drugs, or other therapeutic chemicals, through the skin and into thebody. Therefore, the wrap 18 should act as a wick that negligibly, if atall, restricts flow of medicament ions from the reservoir 12 to thebody.

Examples of suitable materials for the wrap 18 include non-woven blendsof polyester and cellulose, such as Durx® 670 or Durx® 770, which areavailable from Berkshire Corporation of Great Barrington, Mass. Otherexamples of suitable materials for the wrap 18 include blends ofcellulose and polyethylene terephthalate, such as Unilayer® 1+2 orUnispun® 200, which are available from Midwest Filtration Company ofFairfield, Ohio Still further examples of suitable materials for thewrap 18 include various non-woven and interlining fabrics available fromHollingsworth & Vose Company of Floyd, Va.

The adhesive covering 20 is an adhesive tape that serves as a structuralsupport component of the electrode 10 and is also useful for securingthe electrode 10 to the skin. The adhesive covering 20 also preventsseepage of electrolytic solution along the skin away from the electrode10. The adhesive covering 20 should be highly flexible so that thecovering readily conforms to the skin. The adhesive covering 20 may beformed of any suitable material, such as a thin layer of polyvinylchloride foam that is coated with pressuresensitive adhesive. It is tobe understood that other suitable flexible materials that are coatedwith adhesive may be used to form the adhesive covering 20.

Throughout the drawings, like elements are referred to using likereference characters.

The electrode 10 may be modified to form an electrode 110, as in FIG. 2,by replacing the wicking wrap 18 of the electrode 10 with a conductiveadhesive layer 122. In the electrode 110, the conductive adhesive layer122 is placed between and in contact with the reservoir 12 and theconductive layer 14. The function of the conductive adhesive layer 122,similar to the function of the wrap 18, is to aid in holding thereservoir 12 and the conductive layer 14 together. With this structure,the reservoir 12 of the electrode 110 is in direct contact with the bodywhen the electrode 110 is placed against the body.

To prevent degradation of the electrochemical characteristics of theelectrode 110, the conductive adhesive layer 122 should be impermeableto the electrolytic solution that is held in the reservoir 12. Examplesof suitable impermeable materials for use as the conductive adhesivelayer 122 include any of the ARCLAD 8000 series adhesives available fromAdhesive Research, Inc. of Glen Rock, Pa; VERA-TEC adhesive, availablefrom Con-Med Corporation of Utica, N.Y.; Type CMI 107-25 carbon andsilver filled acrylic adhesive, available from Creative Materials, Inc.of Tyngsboro, Mass.; and Type 102-32 silicone-based adhesive, alsoavailable from Creative Materials, Inc.

When used in the electrode 110, the reservoir 12 accepts and holds theelectrolytic solution. In the electrode 110, only the reservoir 12contains electrolytic solution. The reservoir 12 of the electrode 110may hold the electrolytic solution both prior to and during use of theelectrode 110 to deliver any medicament ions through the skin and intothe body of the patient. When used in the electrode 110, the reservoir12 should contain at least enough of the medicament ions for one sessionof patient treatment.

Alternatively, the electrode 10 may be modified to form an electrode210, as depicted in FIG. 3. The electrode 210 includes only a reservoir212 between the adhesive cover 20 and the body. The electrode 210, ascompared to the electrode 10 of FIG. 1, does not include the conductivelayer 14 or the wicking wrap 18. The electrode 210, as compared to theelectrode 110 of FIG. 2, does not include the conductive layer 14 or theconductive adhesive layer 122. When the electrode 210 is placed againstthe skin, the reservoir 212 is in direct contact with the skin.

The reservoir 212 accepts and holds the electrolytic solution. Thereservoir 212 may hold the electrolytic solution both prior to andduring use of the electrode to deliver any medicament ions through theskin of the patient. In the electrode 210, only the reservoir 212contains electrolytic solution. The reservoir 212 should contain atleast enough medicament ions for one session of patient treatment.

It should be understood that both electrodes (not shown) of theiontophoresis system (not shown) may have the structure of the electrode10, the electrode 110, or the electrode 210. Alternatively, either ofthe two electrodes of the iontophoresis system may have, in anycombination, the structure of the electrode 10, the structure of theelectrode 110, the structure of the electrode 210 or a structure that isdifferent from that of the electrode 10, the electrode 110, and theelectrode 210. For example, one of the electrodes of the iontophoresissystem may have the structure of the electrode 10 and the otherelectrode of the iontophoresis system may have the structure of theelectrode 210. As another example, one of the electrodes of theiontophoresis system may have the structure of the electrode 110 and theother electrode of the iontophoresis system may have a structure that isdifferent from the structure of the electrode 10, the electrode 110, andthe electrode 210.

No matter whether the wrap 18 or the conductive adhesive layer 122 isused, the electrode 10 and the electrode 110 are each simpler inconstruction than existing electrodes. For example, some existingelectrodes include four separate components between an adhesiveattachment component and the skin, whereas the electrode 10 and theelectrode 110 include only three separate components between theadhesive cover and the skin. The electrode 210 of FIG. 3 is even simplerthan the electrode 10 and the electrode 110 depicted in FIGS. 1 and 2,respectively, since the electrode 210 of FIG. 3 includes only onecomponent between the adhesive cover 20 and the skin.

The reservoir 212 has the same compositional and structural features asthe reservoir 12, with the exception that carbonized particles areincorporated and immobilized in the reservoir 212 to make the reservoir212 conductive. In the electrode 210, the conductive terminal 16 isattached to the reservoir 212 to direct current flow into the reservoir212. The reservoir 212 conducts current that is applied to the terminal16. The current in the reservoir 212 provides the motive force thatdrives the medicament ions in the reservoir 212 into the body.

The carbonized particles, such as conductive forms of carbon black, maybe homogeneously incorporated throughout the reservoir 212.Additionally, the carbonized particles should have a shape and size thatis adequate to immobilize the carbonized particles within the reservoir212. When the carbonized particles are homogeneously incorporated in thereservoir 212, the incorporation should be accomplished so that theimpedance of the reservoir 212 substantially matches the impedance ofthe skin. If the impedance of the reservoir 212 does not substantiallymatch the impedance of the skin, electrical irritation or burning of theskin may result from use of the reservoir 212 that includeshomogeneously incorporated carbonized particles.

Alternatively, the carbonized particles may be incorporated in thereservoir 212 of the electrode 210 to create an electric potentialbetween an upper surface 224 and a lower surface 226 of the reservoir212. The carbonized particles should have a shape and size that isadequate to immobilize the carbonized particles within the reservoir212. If the anode of the iontophoresis system is structured like theelectrode 210, the electric potential should decrease between thesurface 224 and the surface 226. If the cathode of the iontophoresissystem is structured like the electrode 210, the electric potentialshould increase between the surface 224 and the surface 226. Thecarbonized particles may be distributed within the reservoir 212 orconcentrated proximate the upper surface 224, as appropriate, togenerate the change in potential needed for the anode and the cathode tofunction in the iontophoresis system. The carbonized particles shouldnot be concentrated proximate the lower surface 226 of the reservoir212, since such concentration proximate the lower surface 226 wouldcreate an impedance gradient between the lower surface 226 and the skinthat may cause electrical irritation or burning of the skin.

Current entering the reservoir 212 should be uniformly distributedacross the reservoir 212. Preferably, the current density proximate theinterface of the reservoir 212 and the skin does not exceed about 0.5milliamperes per square centimeter. Current densities proximate the skinof higher than about 0.5 milliamperes per square centimeter increase thelikelihood of patient discomfort and irritation of the skin.

The reservoir 212 of the electrode 210 may be formed of any suitablematerial, such as the permeable material of the reservoir 12.Preferably, the permeable material used to form the reservoir 212includes or consists entirely of the proton sponge, such as theheterogeneous proton sponge foam, or the ion-exchange material, such asthe ion-exchange copolymer or the heterogeneous ion-exchange foam. Thus,the reservoir 212 preferably includes pH buffer material that isimmobilized within the reservoir 212 and that is capable of neutralizinghydrogen ions or hydroxide ions generated by electrolysis of water inthe iontophoresis system. Alternatively, the permeable material used toform the reservoir 212 may consist of or incorporate any combination ofthe ionexchange material and the proton sponge. It is to be understoodthat any ionexchange material and/or proton sponge that is included inthe layer(s) of the reservoir should be immobilized in the layer(s) toprevent movement of any included ion-exchange material or proton spongewithin the reservoir 212.

When the electrode 210 is incorporated in the iontophoresis system (notshown) and is buffered to neutralize adverse ions generated duringelectrolysis of water, the reservoir 212 incorporates the pH buffer thatneutralize any hydrogen ions or hydroxide ions generated in thereservoir 212. If the anode of the iontophoresis system is structuredlike electrode 210, basic elements included in the reservoir 212neutralize hydrogen ions generated at the anode. Conversely, if thecathode of the iontophoresis system is structured like the electrode210, acidic elements included in the reservoir 212 neutralize hydroxideions generated at the cathode.

All subsequent statements about the electrode 10 apply equally to theelectrode 110 and the electrode 210, unless otherwise indicated. Also,all subsequent statements about the reservoir 12 apply equally to thereservoir 212, unless otherwise indicated.

Though prior comments about the iontophoresis system mention delivery ofmedicament ions from one or the other of the electrodes that isstructured like the electrode 10, both iontophoresis system electrodesmay be used to deliver medicament ions. When each electrode of theiontophoresis system delivers medicament ions to the body, those skilledin the art will readily recognize that each electrode of theiontophoresis system acts as the active electrode for the respectivemedicament ions delivered from the respective electrode of theiontophoresis system. Similarly, each electrode of the iontophoresissystem acts as the ground electrode for the respective electrode of theiontophoresis system that is delivering medicament ions to the body.

One necessary step in making the electrode 10 is to obtain the permeablematerial that is used to make the reservoir 12. As noted, one type ofion-exchange copolymer may be formed by reacting a first prepolymer anda second prepolymer. The first and second prepolymers may be polymerizedto form the ion-exchange copolymer using any conventionalcopolymerization technique that is suitable for polymerizing prepolymersthat are used to make the copolymer. The first prepolymer may consist ofa single monomeric precursor or may consist of a mixture of differentmonomeric precursors. Examples of monomeric precursors suitable for useas the first prepolymer include alkanes, alkenes, and substitutedbenzenes, such as divinyl benzene.

The second prepolymer may generally be any single monomeric ion-exchangeprecursor or a mixture of different monomeric ion-exchange precursors.Monomeric ion-exchange precursors may be formed by attaching one or moreion-exchange functional groups to any monomeric precursors using anyconventional chemical bonding technique, such as substitution orgrafting. At least one of the monomeric precursors that acts as thefirst prepolymer and at least one of the monomeric precursors that isused in forming the monomeric ion-exchange precursor should be differentfrom each other.

Examples of monomeric precursors suitable for use in making themonomeric ion-exchange precursor include substituted benzenes, such asdivinyl benzene. Other examples of monomeric precursors suitable for usein making the monomeric ion-exchange precursor include a variety ofurethanes, which may be include a variety of different functionalgroups, such as (1) diol groups and diisocyanate groups and (2) triolgroups and tri-isocyanate groups. Examples of ion-exchange functionalgroups that are suitable for attachment to the monomeric precursor(s)include carboxyl groups, amino groups, --SO₃ H groups, --OPO₃ H₂ groups.Thus, some examples of the monomeric ion-exchange precursor, i.e. thesecond prepolymer, are acrylic acid and methacrylic acid.

One suitable ion-exchange copolymer is prepared by copolymerizingdivinyl benzene, which serves as the first prepolymer, and methacrylicacid, which serves as the second prepolymer. One suitable copolymer ofmethacrylic acid and divinyl benzene is represented by structuralformula I below: ##STR4##

One example of the methacrylic acid/divinyl benzene copolymer withformula I structure is Amberlite® IRP-64, which is available from Rohm &Haas Co. of Philadelphia, Pa. Amberlite® IRP-64 has an x/y ratio of 12.Thus, an average monomer unit of the Amberlite® IRP-64 copolymer has 24methacrylic acid groups per divinyl benzene group. Additionally, theAmberlite® IRP-64 copolymer is about 4.5% by weight divinyl benzene andabout 95.5% by weight methacrylic acid. The Amberlite® IRP-64 copolymermay be part or all of the permeable material used to form the reservoir12 when the cathode of the iontophoresis system has the structure of theelectrode 10.

When the anode of the iontophoresis system has the structure of theelectrode 10, the permeable material of the reservoir 12 may be or mayinclude a metal salt of the ion-exchange copolymer. The ion-exchangecopolymer may be treated with a mineral acid, such as potassiumchloride, to obtain the metal salt of the ion-exchange copolymer.Treatment of the copolymer of graphic formula I with potassium chlorideyields the compound represented by graphic formula II, which is oneexample of a suitable metal salt of the ion-exchange copolymer: ##STR5##

One example of the copolymer metal salt with the formula II structure isAmberlite® IRP-88, which is available from Rohm & Haas Co. Amberlite®IRP-88 has an x/y ratio of 12. Thus, an average monomer unit of theAmberlite® IRP-88 copolymer has 24 metal salt groups of methacrylic acidper divinyl benzene group. The Amberlite® IRP-88 copolymer may be partor all of the permeable material of the reservoir 12 when the anode ofthe iontophoresis system has the structure of the electrode 10.

One preferred formulation of the ion-exchange copolymer is aurethane/methacrylic acid copolymer with the structure represented ingraphic formula III: ##STR6##

One suitable urethane/methacrylic acid copolymer with the structure offormula III may be manufactured by copolymerizing methacrylic acid witha suitable polyurethane prepolymer, such as a foamable polyurethaneprepolymer that is derived from toluene diisocyanate. Methacrylic acidmay be obtained from Ashland Chemical Company of St. Paul, Minn. or fromRohm & Haas Co. of Philadelphia, Pa. Foamable polyurethane prepolymerthat is derived from toluene diisocyanate is marketed as part of theHypolb group of products by W. R Grace & Company of Woburn, Mass. Someexamples of suitable Hypol® polyurethane prepolymers include Hypol® FHP2000, Hypol® FHP 2002, and Hypol® FHP 3000.

The urethane/methacrylic acid copolymer with the structure of formulaIII is preferably from about 65% to about 85% by weight urethane andfrom about 15% to about 35% by weight methacrylic acid. Theurethane/methacrylic acid copolymer with the structure of formula IIImay be part or all of the permeable material used to form the layer(s)of reservoir 12 when the cathode of the iontophoresis system has thestructure of the electrode 10.

When the anode of the iontophoresis system has the structure of theelectrode 10, the permeable material of the reservoir 12 may be or mayinclude a metal salt of the urethane/methacrylic acid copolymer ofFormula III. One suitable salt of the urethane/methacrylic acidcopolymer of Formula III has the structure of graphic formula IV:##STR7## The salt with the structure of graphic formula IV may be formedby treating the urethane/methacrylic acid copolymer of graphic formulaIII with a suitable mineral acid, such as potassium chloride.Preferably, the mineral acid treatment converts from about 25% to about45%, by weight, of the carboxylic functionalities of the formula IIIurethane/methacrylic acid copolymer to the copolymer metal salt offormula IV.

Another preferred formulation of the ion-exchange copolymer isurethane/carboxylic acid copolymer. Suitable urethane/carboxylic acidcopolymer may be manufactured by copolymerizing polyacrylic acidprepolymer or polycarboxylic acid prepolymer with a suitablepolyurethane prepolymer, such as the foamable polyurethane prepolymerthat is derived from toluene diisocyanate. Suitable polyacrylic acidprepolymer and suitable polycarboxylic acid prepolymer are marketed aspart of the Tamol®, Acusol®, and Acumer® product groups by Rohm & HaasCo. of Philadelphia, Pa. Some examples of suitable Tamol® prepolymersinclude Tamol® 850, Tamol® 960, Tamol® 963, and Tamol® 983. Someexamples of suitable Acusol® prepolymers include Acusol® 445 and Acusol®445N. One example of a suitable Acumer® prepolymer is Acumer® 1510. Asmentioned, foamable polyurethane prepolymer that is derived from toluenediisocyanate is marketed as part of the Hypol® group of products by W. RGrace & Company of Woburn, Mass.

When the anode of the iontophoresis system has the structure of theelectrode 10, the permeable material of the reservoir 12 may be or mayinclude a metal salt of the urethane/carboxylic acid copolymer. Themetal salt of the urethane/carboxylic acid copolymer may be formed bytreating the urethane/carboxylic acid copolymer with a suitable mineralacid, such as potassium chloride. Preferably, the mineral acid treatmentconverts from about 25% to about 45%, by weight, of the carboxylicfunctionalities of the urethane/carboxylic acid copolymer to the metalsalt form of the urethane/carboxylic acid copolymer.

As noted, the permeable material of the reservoir 12 may also be formedfrom or may include heterogeneous ion-exchange foam. The heterogeneousion-exchange foam should preferably have a uniform pH ranging from about4 to about 8 to avoid irritating or burning the skin. The heterogeneousion-exchange foam includes the polymer or copolymer foam portion and oneor more organic ion-exchange substances that are dispersed in thepolymer or copolymer foam portion. The molecular weight of any organicion-exchange substances that are incorporated in the polymer orcopolymer foam portion should be at least about 5000 daltons (grams permole) to immobilize the organic ion-exchange substance(s) in theheterogeneous ion-exchange foam.

The organic ion-exchange substances are dispersed in one or moreprepolymer components of the polymer foam or the copolymer foam prior toreacting the prepolymer components to make the polymer or copolymerfoam. After formation of the heterogeneous ion-exchange foam, thepolymer or copolymer foam and the organic ion-exchange substance(s) formdistinct phases of the heterogeneous ion-exchange foam. Additionally,the organic ion-exchange substance(s) are physically entrapped withinthe structure of the polymer or copolymer foam.

Examples of suitable ion-exchange substances, for use in making theheterogeneous ion-exchange foam, include various anion and cationexchange resins, in either gel or macroreticular form, such as theAmberlite® series of resins and the Duolite® series of resins availablefrom Rohm & Haas Corporation and the Dowex® series of resins availablefrom Dow Corporation of Midland, Mich. Examples of suitable Amberlite®resins include Amberlite® IRP-64, Amberlite® IRP-68, Amberlite® IRP-88,Amberlite® CG-50 and Amberlyst®A21. Examples of suitable Duolite® resinsinclude Duolite® C433, Duolite® A-368, and Duolite® A-392S. Examples ofsuitable Dowex® resins include Dowex® WGR, Dowex® WGR-Z, and Dowex®MWA-1. To aid in attaining the about 4 to about 8 pH range in theheterogeneous ion-exchange foam, the ion-exchange resin shouldpreferably be either weakly basic or acidic, be of fine particle size,and be pharmaceutical-grade gel-type resin.

Examples of prepolymer that are suitable for use in making heterogeneousion-exchange foam include polyurethane prepolymer, polyester prepolymer,and polystyrene prepolymer. One example of a suitable polyurethaneprepolymer is foamable polyurethane prepolymer that is derived fromtoluene diisocyanate. Suitable examples of the foamable toluenediisocyanate-derived polyurethane prepolymer include prepolymers of theHypol® series that are available from W. R Grace & Company of Woburn,Mass. Some examples of suitable Hypol® polyurethane prepolymers includeHypol® FHP 2000, Hypol® FHP 2002, and Hypol® FHP 3000. Polyurethaneprepolymers other than these Hypol® prepolymers my be used, but notnecessarily with equivalent results.

The heterogeneous ion-exchange foam may be prepared and formed into thelayer(s) of the reservoir 12 using any suitable procedures. Generally,preparation of the heterogeneous ion-exchange foam involves (i)dispensing and mixing of the ingredients (i.e. prepolymer andion-exchange substance) of the heterogeneous ion-exchange foam, (ii)blowing, such as by incorporating a blowing agent that is capable ofpromoting a suitable blowing reaction, such as a creaming reaction,rising reaction, or a full rise reaction, and (iii) gelling, such as viagelling reaction. After preparation, the foam is subjected to a suitableshaping process, such as extrusion, injection molding, compressionmolding, injection compression molding, or transfer molding, and issubsequently cured to form the layer(s) of the reservoir 12.

During preparation of the heterogeneous ion-exchange foam, the rate ofthe blowing reaction and the rate of the gelling reaction is determinedby catalyst incorporated in the reaction. Examples of the catalystinclude tertiary amines, which promote blowing reactions, andorganometallics, which promote gelling reactions. Tertiary amines mayalso help enhance blowing reaction rate, and organometallics may alsohelp enhance gelling reaction rate. Additional blowing beyond thatattributable solely to the blowing reaction may be obtained byincorporating an auxiliary blowing agent, such as methylene chloride ora suitable chlorofluorocarbon, such as CFC-11. The use of asilicone-based surfactant will help selectively control cell size anduniformity in the foam by reducing surface tension of the foamingredients. The silicone-based surfactant may also enhancesolubilization of the foam ingredients.

One example of another suitable procedure for forming the heterogeneousion-exchange foam entails mixing any selected ion-exchange substance(s)with water to form an aqueous suspension. Preferably, the ion-exchangesubstance(s) is in the form of fine powder to enhance the distributionof the ion-exchange substance in the heterogeneous ion-exchange foam andto enhance the surface area that is available for ion-exchange. Theaqueous suspension is combined with the prepolymer component(s) of thefoam, such as any of the noted Hypol® prepolymers, with rapid stirringto form a foam mixture. The foam mixture is further agitated untilexpansion due to foaming subsides. The foam mixture is subjected to asuitable shaping process, such as extrusion, injection molding,compression molding, injection compression molding, or transfer molding,and is subsequently cured to form the layer(s) of the reservoir 12.

The pH buffering reactions occurring in the anode and the cathode of theiontophoresis system, when the reservoir 12 is made of or includeseither the ion-exchange copolymer or the heterogeneous ion-exchangefoam, may be generally characterized as ion-exchange reactions. pHbuffering reactions of any proton sponge included in the reservoir 12are properly characterized as ion scavenging reactions, and notion-exchange reactions.

As noted, hydrogen ions (H⁺) are evolved at the positive electrode(anode) and hydroxide ions (OH⁻) are evolved at the negative electrode(cathode) by electrolysis of water. Ion-exchange reactions occurring atthe anode neutralize hydrogen ions (H⁺) contained in the electrolyticsolution and ionexchange reactions occurring at the cathode neutralizehydroxide ions (OH⁻) contained in the electrolytic solution.

More particularly, the ion-exchange reaction that occurs in the anodethat has the structure of the electrode 10, when the reservoir 12 isformed of or includes the ion-exchange copolymer or the heterogeneousion-exchange foam, may be characterized according to reaction (1) asfollows:

    --COOK+H.sup.+ →--COOH+K.sup.+,                     (1)

where --COOK represents one example of a suitable ion-exchangefunctionality of either the ion-exchange copolymer or the heterogeneousion-exchange foam and where --COOH represents the carboxyl group.Additionally, H⁺ represents hydrogen ion generated by electrolysis ofwater at the anode, and K⁺ represents a potassium ion that is releasedfrom the ion-exchange functionality by the ionexchange reaction thatneutralizes hydrogen ion (H⁺). Potassium ion (K⁺) is an example of theadverse ion that is not intended for delivery into the human or animalbody. Of course, it is be understood that the ion-exchange functionalityincorporated in the electrode 10 may be other than the --COOKfunctionality and that the ion released from the ion-exchangefunctionality during the ion-exchange reaction in the anode may be otherthan K⁺.

Where the ion-exchange reaction occurs in accordance with reaction (1),it has been found that potassium ions (K⁺) that are released by theion-exchange reaction into the electrolytic solution are about fivetimes less mobile than are hydrogen ions (H⁺). As a result, theundesirable competitive effect between the potassium ion and medicamentions to be delivered to the body is significantly reduced, as comparedto the competitive effect between hydrogen ion (H⁺) and the medicamentions to be delivered to the body. Therefore, the efficiency ofmedicament ion delivery to the body is considerably improved when the--COOK functionality is incorporated in the reservoir 12 via either theion-exchange copolymer or the heterogeneous ion-exchange foam.Furthermore, neutralization of the hydrogen ion (H⁺) makes it possibleto maintain the pH at between about 4 and about 8 in the electrolyticsolution of the anode that is structured like the electrode 10.

Though the ion-exchange functionality employed at the anode may be otherthan --COOK and though the adverse ion that is released from theionexchange functionality may be other potassium ion (K⁺), theion-exchange functionality that is selected should release an ion thatis at least two times less mobile in the electrolytic solution thanhydrogen ion. Preferably, the ionic functionality is selected so thatthe ion released from the ion-exchange functionality has the samemobility or less mobility in the electrolytic solution than potassiumion.

The ion-exchange reaction that occurs in the cathode that is structuredlike the electrode 10, when the reservoir 12 is formed of or includesion-exchange copolymer or heterogeneous ion-exchange foam, actuallyconsists of two separate reaction sequences that may be characterized asreaction (2) and reaction (3) as follows:

    --COOH+M.sup.+ →--COOM+H.sup.+                      (2)

    H.sup.+ OH.sup.- H.sub.2 O,                                (3)

In reaction (2), --COOH represents the ion-exchange functionality of theion-exchange copolymer or the heterogeneous ion-exchange foam includedin the reservoir 12 of the electrode 10 that serves as the cathode, andM+represents metal ion released from the ionic substance by dissociationof the ionic substance in the electrolytic solution of the cathode. Asan example, the metal ion released upon dissociation of dexamethasonedisodium phosphate, one example of the ionic substance, is sodium ion(Na⁺). Also, in reaction (2) and reaction (3), H⁺ represents thehydrogen ion released by the ionic functionality during reaction (2) andOH⁻ represents the hydroxide ion generated by electrolysis of water atthe cathode. Of course, it is to be understood that the ion-exchangefunctionality incorporated in the ion-exchange copolymer or theheterogeneous ion-exchange foam of the cathode may be other than --COOHand that the ion released upon dissociation of the ionic substance inthe cathode may be other than metal ion (M⁺). The metal ion (M⁺)depicted in reaction (2) that evolves on dissociation of the ionicsubstance is another example of the complimentary ion that is notintended for delivery into the human or animal body.

The net result of reaction (2) and reaction (3) is that hydrogen ion(H⁺) released from the ionic functionality of the cathode reacts withthe hydroxide ion (OH⁻) generated by electrolysis of water at thecathode to produce water (H₂ O). Since the metal ion (M⁺) that isdissociated from the ionic species exchanges with the hydrogen ion H⁺ inreaction (2), the net effect of reaction (2) and reaction (3) is that noadverse or complimentary ion depicted in reaction (2) or reaction (3)remains in the electrolytic solution to compete with the medicament ionsfor delivery to the body.

In another embodiment of the electrode 10, the permeable material of thereservoir 12 is made of or incorporates any suitable proton sponge. Asmentioned, Type A, Type B, and Type C proton sponges are some of theproton sponges of interest. The Type A proton sponge may be prepared byincorporating two or more proton sponge functional groups onto thecarrier compound. Each proton sponge functional group consists of a pairof neighboring proton sponge functional group components. The protonsponge functional group components are attached to the carrier compoundso that the proton sponge functional group components cooperate togetherand form the proton sponge functional group.

Tertiary amino groups, such as dialkyl amino groups and di-alkylpyridinegroups are examples of suitable proton sponge functional groupcomponents for the Type A proton sponge. The diethyl amino group and thedimethyl amino group are examples of suitable dialkyl amino groups, andthe di-methylpyridine group and the di-butylpyridine group are examplesof suitable di-alkylpyridine groups. Another example of suitable protonsponge functional group components include certain phosphino groups,such as diphenyl phosphino groups.

Assuming for purposes of illustration that the proton sponge functionalgroup components are tertiary amino groups, the tertiary amino groupscreate strain within the proton sponge which causes the proton sponge toexhibit steric effects. The steric effects cause the proton sponge to bemore strongly basic than would be expected from the mere presence of thetwo tertiary amino groups. Protonation of the proton sponge withhydrogen ion relieves the steric strain and stabilizes the protonsponge. The hydrogen ion resonates between covalent bonding and hydrogenbonding to the nitrogens of the diethyl amino groups such that, at anyparticular time, the hydrogen ion forms a hydrogen bond with thenitrogen of one of the diethyl amino groups and forms a covalent bondwith the nitrogen of the other of the diethyl amino groups.

The carrier compound of the Type A proton sponge may be any organiccompound, such as a homocyclic compound, a heterocyclic compound, or astraight or branched organic chain that may, optionally, include heteroatoms in the chain. Additionally, the carrier compound may be anysuitable polymer of the homocyclic compound, the heterocyclic compound,or the straight or branched organic chain. To be useful in forming theType A proton sponge, proton sponge functional group components shouldbe capable of being attached to the carrier compound in neighboring,strained relation to make the proton sponge. The carrier compound maytake any physical form, provided that the carrier compound should beinsoluble in the solvent of the electrolytic solution and provided thatthe carrier compound should prevent physical movement, such asdiffusion, migration, and electro-migration, of the proton sponge withinthe electrode 10.

Some examples of organic compounds that are suitable for use as thecarrier compound include naphthalene, fluorene, phenanthrene, andisoindene. An example of the Type A proton sponge that includes fluoreneas the carrier compound is 4,5bis(dimethylamino)fluorene. An example ofthe Type A proton sponge that includes phenanthrene as the carriercompound is 4,5-bis(dimethylamino)phenantlrene.

The carrier compound of the Type A proton sponge may also be a copolymerof any two or more different organic compounds. Examples of organiccompounds that may be used in forming the copolymer that is useful asthe carrier compound include homocyclic compounds, heterocycliccompounds, or straight or branched organic chains that may, optionally,include hetero atoms in the chain. To be suitable for use as the carriercompound, the copolymer should permit attachment of the proton spongefunctional group components in neighboring, strained relation to makethe proton sponge. Naphthalene/urethane copolymer is an example of thecopolymer that may serve as the carrier compound. For thenaphthalene/urethane copolymer, suitable proton sponge functional groupcomponents, such as diethyl amino groups, may be attached to thenaphthalene group in neighboring, strained relation.

As mentioned, the Type B proton sponge may be prepared by incorporatingone or more pairs of hetero atoms into the organic core compound atselect positions. In the Type B proton sponge, the shape of the organiccore compound places the pair of hetero atoms relatively close togetherand hinders movement of reactants toward the hetero atoms. Protonationof the Type B proton sponge, such as addition of hydrogen ion betweenadjacent hetero atoms, stabilizes the Type B proton sponge and enablesfurther ionic reaction of the protonated Type B proton sponge. Theorganic core compound may take any physical form, provided that theorganic core compound should be insoluble in the solvent of theelectrolytic solution and provided that the organic core compound shouldprevent physical movement, such as diffusion, migration, andelectro-migration, of the proton sponge within the electrode 10.

Some examples of the Type B proton sponge include quino 7,8-h!quinoline,phenanthroline and piperazinyl-naphthyridine. The organic core compoundmay be any combination of two or more ring compounds, such as pyrol,pyridine, or similar. The organic core compound may be any suitablepolymer or copolymer that includes adjacent ring compounds. In the TypeB proton sponge, nitrogen is substituted in place of carbon inrespective rings of at least two adjacent ring compounds so thatadjacent ring nitrogens are spaced in close relation to each other andhinder movement of molecules toward the ring nitrogens of the Type Bproton sponge.

As mentioned, the Type C proton sponge may be characterized as theorganic support compound that includes at least one hetero atom and atleast two attached organic groups. The hetero atom is substituted intothe organic support compound in place of carbon. Each of the two organicgroups are attached to ring or chain carbons that are next to, and onopposing sides of, the hetero atom. With this structure, the twoattached organic groups surround and closely confront the hetero atom.

Benzene-based monomers are some examples of the organic supportcompound. Other examples of the organic support compound includesuitable polymers or copolymers, such as polymers or copolymers thatinclude organic rings, including benzene. The organic support compoundmay take any physical form, provided that the organic support compoundshould be insoluble in the solvent of the electrolytic solution andprovided that the organic support compound should prevent physicalmovement, such as diffusion, migration, and electro-migration, of theproton sponge within the electrode 10.

2,6-di-t-butylpyridine is one example of the Type C proton sponge. Inthe Type C proton sponge that is 2,6-di-t-butylpyridine, pyridine is theorganic support compound. Assuming that nitrogen is at the No. 1position of the ring, 2,6-di-t-butylpyridine may be prepared byattaching tertiary-butyl groups to the No. 2 and the No. 6 positions ofthe ring, adjacent to, and on either side of the ring nitrogen.

In the Type C proton sponge, the bulky nature of the organic groups thatare attached on opposing sides of the hetero atom, such as nitrogen,hinders movement of reactants toward the hetero atom. Protonation ofType C proton sponges, such as addition of hydrogen ion to the heteroatom, such as by covalent bonding, stabilizes the Type C proton spongesand enables further ionic reaction of the protonated Type C protonsponge.

Additional techniques for forming the Type A proton sponge areenvisioned. It has been found that proton sponge functional groupcomponents, paired in neighboring, strained relation as the protonsponge functional group, may be incorporated into the carrier compoundto make the proton sponge in a variety of ways. For example, one or morepairs of proton sponge functional group components may be attached, suchas by substitution, in neighboring, strained relation onto a monomericprecursor to make a monomeric sponge group precursor. The monomericsponge group precursor is then reacted with one or more secondarymonomeric precursors to form a proton sponge copolymer that incorporatesthe proton sponge functional group. The secondary monomeric precursormay generally be any polymerizable compound, such as polymerizablearomatic compounds, polymerizable homocyclic compounds, polymerizableheterocyclic compounds, or polymerizable straight or branched organicchains.

Each monomeric sponge group precursor of the proton sponge copolymer mayhave the same matched pairs of proton sponge functional groupcomponents. Alternatively, there may be two or more different monomericsponge group precursors that each may include two or more differentmatched pairs of proton sponge functional group components. Also, onesecondary monomeric precursor may be copolymerized with the monomericsponge group precursor(s) to make the proton sponge copolymer.Alternatively, two or more different secondary monomeric precursors maybe copolymerized with the monomeric sponge group precursor(s) to makethe proton sponge copolymer. The secondary monomeric precursor(s) may becopolymerized with the monomeric sponge group precursor(s) to form theproton sponge copolymer using any conventional copolymerizationtechnique that is suitable for polymerizing precursors included in theproton sponge copolymer.

A polymerizable monomer, such as a polymerizable naphthalene-basedmonomer, that includes a pair of substituted proton sponge groupcomponents is one example of the monomeric sponge group precursor of theproton sponge copolymer. Though some monomers, such as anaphthalene-based compound that includes only a single naphthalene groupper molecule, may accommodate only a single pair of proton sponge groupcomponents, other polymerizable monomers that may include two or morepairs of proton sponge group components may be used as the monomericsponge group precursor of the proton sponge copolymer. Additionalexamples of monomers that may be suitably combined with proton spongefunctional group components to make the monomeric sponge group precursorinclude polymerizable fluorene-based compounds, polymerizablephenanthrene-based compounds, polymerizable isoindene-based compounds,and any other polymerizable compound that is capable of forming astructural network that imposes a close proximity, strained formation onneighboring pairs of proton sponge functional group components.

Other possibilities for forming the Type A proton sponge exist. Forexample, matched pairs of proton sponge functional group components, orany monomeric sponge group precursor, may be chemically attached to thecarrier compound to make a substituted proton sponge polymer orcopolymer.

Examples of the carrier compound suitable for making the substitutedproton sponge polymer include various polymers, such as homopolymersbased on naphthalene; fluorene; phenanthrene; isoindene; variousurethanes, such as etheric and esteric urethanes; vinyl alcohol; vinylpyrolidone; acryl amide; carbohydrate; ethylene oxide; andhydroxyalkylmethacrylate. Examples of the carrier compound suitable formaking the substituted proton sponge copolymer include variouscopolymers, such as copolymers based on any two or more of thefollowing: naphthalene; fluorene; phenanthrene; isoindene; variousurethanes, such as etheric and esteric urethanes; vinyl alcohol; vinylpyrolidone; acryl amide; carbohydrate; ethylene oxide; andhydroxyalkylmethacrylate. As an example, naphthalene/urethane copolymermay be used as the carrier compound of the substituted proton spongecopolymer. Examples of functional groups for the urethane that may beused in making the substituted proton sponge polymer or copolymerinclude (1) diol groups and diisocyanate groups and (2) triol groups andtri-isocyanate groups.

Examples of proton sponge functional group components suitable forchemical attachment onto the carrier compound to make the substitutedproton sponge polymer or the substituted proton sponge copolymer includetertiary amino groups, such as dialkyl amino groups and di-alkylpyridinegroups. The diethyl amino group and the dimethyl amino group areexamples of suitable dialkyl groups, and the di-methylpyridine group andthe di-butylpyridine group are examples of suitable di-alkylpyridinegroups.

The proton sponge of the present invention may also be heterogeneouslyincorporated in suitable foam to make a heterogeneous proton spongefoam. Heterogeneous proton sponge foam is made by dispersing the protonsponge in one or more prepolymer components of polymer or copolymerfoam, prior to reacting the prepolymer components to make the polymer orcopolymer foam. In the heterogeneous proton sponge foam, the protonsponge is physically entrapped within the structure of the polymer orcopolymer foam. The molecular weight of the proton sponge that isincorporated in the polymer or copolymer foam should be at least about5000 daltons (grams per mole) to immobilize the proton sponge in thepolymer or copolymer foam. Preferably, the polymer or copolymer foamportion of the heterogeneous proton sponge foam is an open cell foamthat supports enhanced movement of the electrolytic solution within theheterogeneous proton sponge foam.

After formation of the heterogeneous proton sponge foam, the polymer orcopolymer foam and the proton sponge form distinct phases of theheterogeneous proton sponge foam. Heterogeneous proton sponge foamincludes at least two distinct phases. For any electrode that includesthe heterogeneous proton sponge foam, each of the phases should beinsoluble in the solvent portion of any electrolytic solution includedin the electrode to immobilize physical movement of any component of theheterogeneous proton sponge foam within the electrode. The phases mayeach be solid or semi-solid in nature. Alternatively, some phase(s) maybe solid in nature, and other phase(s) may be semi-solid in nature. Theproton sponge makes one or more of the phases, and polymer foam orcopolymer foam makes up the other phase(s).

Other examples of heterogeneous proton sponge materials include variouscomposite polymer mixtures of host polymeric material and proton sponge.The host polymeric material may be formed as a gel, a membrane, ahydrocolloid, fibers, a laminate, particles, granules, or other suitablematrix. The proton sponge may be dispersed within the host polymericmaterial, such as by impregnating the proton sponge within the hostpolymeric material either before or after formation of the hostpolymeric material. The molecular weight of the proton sponge that isincorporated in the host polymeric material should be at least about5000 daltons (grams per mole) to immobilize and physically entrap theproton sponge within the host polymeric material. The proton sponge mayalso be coated onto the host polymeric material. When the host polymermaterial is a loose material, such as in the form of particles orgranules, the reservoir 12 may include suitable boundary layers (notshown) for containing the host material within the reservoir 12.

The heterogeneous proton sponge foam may be prepared and formed into thelayer(s) of the reservoir 12 using any suitable procedure. For examplethe heterogeneous proton sponge foam may be prepared and formed usingthe procedures already described for preparing and forming theheterogeneous ion-exchange foam, with the exception that the protonsponge is substituted in place of the ion-exchange substance in theprocess steps. Any proton sponge, such as the Type A proton sponge, theType B proton sponge, and the Type C proton sponge, may be incorporatedin the heterogeneous proton sponge foam. Examples of prepolymer that aresuitable for use in forming the heterogeneous proton sponge foam includeeach of the prepolymers described for use in preparing the heterogeneousion-exchange foam.

Alternatively, homogeneous proton sponge foam may be prepared byintroducing any type or form of the proton sponge, in any combination,onto previously prepared homogeneous foam by suitable surface orpenetrating treatment, provided that the molecular weight of the protonsponge that is used to make the homogeneous proton sponge foam shouldhave a molecular weight of at least about 5000 daltons (grams per mole)to immobilize the proton sponge within the homogeneous proton spongefoam.

Illustrative examples of proton sponges that may be incorporated in thehomogeneous proton sponge foam include any suitable Type A, Type B orType C proton sponges, or a mixture of any of these types of protonsponges. Some particular examples of the proton sponge that be mayintroduced onto the homogeneous foam to make the homogeneous protonsponge foam include 1,8-Bis(diethylamino)-2,7-dimethoxynaphthalene,4,5bis(dimethylamino)fluorene, 4,5bis(dimethylamino)phenanthrene, quino7,8-h! quinoline, phenanthroline, piperazinyl-naphthyridine,2,6-di-t-butylpyridine, derivatives of these, and analogues of these.

Suitable homogeneous foams for use in preparing the homogeneous protonsponge foam include phenol-formaldehyde, polyurethane, polyethylene, andpolyvinyl alcohol. The precursor components of the homogeneous protonsponge foam may be reacted to form the homogeneous proton sponge foamusing any conventional foam formation process that is suitable for theparticular precursor components selected.

It should also be understood that, either before, during, or afterformation of the permeable material, the proton sponge may be dispersedwithin any permeable material in addition to heterogeneous orhomogeneous foam to incorporate the proton sponge in the reservoir 12.Also, either before, during, or after formation of the permeablematerial, proton sponge functional groups or compounds that includeproton sponge functional groups, may be dispersed within any permeablematerial, including heterogeneous and homogeneous foam, to incorporatethe proton sponge functional groups in the reservoir 12 as the protonsponge. The molecular weight of any proton sponge or proton spongefunctional groups that are dispersed in the permeable material should beat least about 5000 daltons (grams per mole) to immobilize the protonsponge or proton sponge functional groups within the permeable material.

Other techniques for incorporating the proton sponge into the electrode10, in addition to dispersing the proton sponge within the permeablematerial, are envisioned. For example, the proton sponge may be placedseparate from the reservoir 12, within the electrode 10 depicted in FIG.1 or the electrode 110 depicted in FIG. 2, as a proton sponge layer (notshown) between the conductive layer 14 and the reservoir 12 and adjacentto the reservoir 12. In this version of the electrode 10 or theelectrode 110, the permeable material used to form the reservoir 12 maybe any conductive material that is capable of accepting the electrolyticsolution. As another example, the proton sponge may be placed within theelectrode 210 depicted in FIG. 3, separate from the reservoir 212, as aproton sponge layer (not shown) that is located between and thereservoir 212 and the adhesive layer 20. In this version of theelectrode 210, the permeable material used to form the reservoir 212 maybe any conductive material that is capable of accepting the electrolyticsolution.

One example of the Type A proton sponge is the copolymer which has thestructure provided in graphic formula V: ##STR8##

The copolymer of formula V is from about 20% to about 30%1,8-di-(diethylamino)-naphthalene, by weight, and from about 70% toabout 80% urethane, by weight. The copolymer of formula V may be formedby substituting the diethyl amino groups onto the naphthalene group toform a substituted naphthalene-based compound before copolymerizing thesubstituted naphthalene-based compound and the urethane compound. Thesubstituted naphthalene-based compound and the urethane compound may becopolymerized using any conventional copolymerization process thatpreserves the structural integrity of the substituted naphthalene-basedcompound. Alternatively, the diethyl amino groups may be substitutedonto the naphthalene group after copolymerizing the naphthalene-basedcompound and the urethane compound. The naphthalene-based compound andthe urethane compound may be copolymerized using any conventionalcopolymerization process.

After scavenging hydrogen ion (H⁺) at the anode, the proton sponge ofgraphic formula V has the protonated structure of graphic VI and is ableto bond with anions, such as chloride ion released on dissociation oflidocaine hydrochloride: ##STR9## In the protonated proton sponge ofgraphic formula VI, the hydrogen ion resonates between covalent bondingand hydrogen bonding to one of the diethyl amino groups and resonatesbetween hydrogen bonding and covalent bonding with the other of thediethyl amino groups. Thus, at any particular time, the hydrogen ionforms a hydrogen bond with the nitrogen of one of the diethyl aminogroups and forms a covalent bond with the nitrogen of the other of thediethyl amino groups. After bonding with the chloride ion that isreleased on dissociation of lidocaine hydrochloride, the protonatedproton sponge of graphic formula VI has the structure of graphic formulaVII: ##STR10## Though the chloride ion has bonded with the protonatedproton sponge, no adverse ions were released by the protonated protonsponge to compete with medicament ions for delivery to the body.

Another example of the Type A proton sponge is 1,8bis (diethylamino)naphthalene, which has the structure of graphic formula VIII: ##STR11##The proton sponge of graphic formula VIII includes naphthalene as thecarrier compound and diethyl amino groups as the matched proton spongefunctional component groups. The proton sponge of graphic formula VIIImay be incorporated into the iontophoresis system in a number of ways.For example, the proton sponge of graphic formula VIII may be covalentlyattached to a suitable polymer or copolymer chain that is subsequentlydispersed within the permeable material that forms the reservoir 12.

No matter how the proton sponge is incorporated in the electrode 10, theelectrode 110, or the electrode 210, the proton sponge functional group,when employed in the anode of the iontophoresis system, effectivelyscavenges hydrogen ions (H⁺) generated at the anode by electrolysis ofwater via a protonation reaction. Using the Type A proton sponge ofgraphic formula VIII for purposes of illustrating the reaction, theprotonation reaction may be represented by reaction (4): ##STR12## Inreaction (4), the Type A proton sponge scavenges hydrogen ion (H⁺)released during electrolysis of water at the anode. The hydrogen ion(H⁺) resonates between covalent bonding (represented by the solid line)and hydrogen bonding to the nitrogen of one of the proton spongefunctional group components and resonates between hydrogen bonding(represented by the dashed line) and covalent bonding to the nitrogen ofthe other of the proton sponge functional group components. Thus, at anyparticular time, the hydrogen ion forms a hydrogen bond with thenitrogen of one of the proton sponge group components and forms acovalent bond with the nitrogen of the other of the proton spongefunctional group components.

Though the proton sponge functional group components in reaction (4) aredepicted as diethyl amino groups, it is to be understood that the protonsponge functional group components involved in reaction (4) may be anysuitable proton sponge functional group components, including diethylamino groups. Also, though the carrier compound in reaction (4) isdepicted as naphthalene, it is to be understood that the carriercompound involved in reaction (4) may be any suitable carrier compound.

The second step of the proton sponge reaction sequence is represented byreaction (5): ##STR13## In reaction (5), the anion, chloride (Cl⁻),combines with the protonated proton sponge to counterbalance thepositively charged protonated proton sponge. The chloride ion (Cl⁻)enters the electrolytic solution when the lidocaine hydrochloridedissociates in the electrolytic solution. It should be understood thatreaction of the protonated proton sponge, as in reaction (5), will varyin extent, depending upon the ionic substance employed at the anode,since some complimentary anions of medicament cations may form insolublesalts with any counter ions present in the electrolytic solution, ratherthan bonding with the protonated proton sponge.

The proton sponge functional group may be incorporated in either theanode or the cathode of the iontophoresis system. However, the protonsponge functional group is most beneficial when incorporated into theanode structured like the electrode 10, since hydrogen ions (H⁺) are nottypically generated at the cathode and since the proton sponge isincapable of scavenging hydroxide ion (OH⁻).

Though the proton sponge functional group in reaction (5) is depicted asa pair of diethyl amino groups, it is to be understood that the protonsponge functional group involved in reaction (5) may be any suitableproton sponge functional group, including a pair of diethyl aminogroups. Also, though the carrier compound in reaction (5) is depicted asnaphthalene, it is to be understood that the carrier compound involvedin reaction (5) may be any suitable carrier compound. Furthermore,though the ionic species in reaction (5) is depicted as lidocainehydrochloride, it is to be understood that the ionic species involved inreaction (5) may be any suitable ionic species, including lidocainehydrochloride, that frees an anion for bonding with the protonatedproton functional sponge.

For the electrode 10 that includes lidocaine hydrochloride as the ionicspecies in the reservoir 12, the proton sponge functional group that isselected should have a dissociation constant, pK_(a), that isapproximately equal to the pK_(a) of lidocaine hydrochloride ofapproximately 8 to minimize, and preferably prevent, conversion of thelidocaine hydrochloride into lidocaine base and to promote protonationof the proton sponge functional group. If the pK_(a) value of the protonsponge functional group is higher than the pK_(a) value of lidocainehydrochloride, the proton sponge functional group tends to attracthydrogen ion (H⁺) from the lidocaine hydrochloride, thus convertinglidocaine hydrochloride into the less beneficial lidocaine base. On theother hand, if the pK_(a) value of the proton sponge functional group issomewhat less than the pK_(a) value of lidocaine hydrochloride,protonation of the proton sponge functional group with hydrogen ion (H⁺)arising from electrolysis of water at the anode tends to decrease inextent.

No matter how the proton sponge functional group is incorporated in theanode of the iontophoresis system, the electrode 10 that includes theproton sponge functional group exhibits superior qualities, even ascompared to the electrode 10 that includes the ion-exchange copolymer orthe heterogeneous ion-exchange foam. Specifically, the proton spongefunctional group, like the ion-exchange copolymer and the heterogeneousion-exchange foam, remedies the pH shift problem found in prior artelectrodes by binding hydrogen ions (H⁺) generated by electrolysis ofwater. Additionally, unlike the ion-exchange copolymer and theheterogeneous ion-exchange foam, the proton sponge functional group doesnot release any ions that will compete with medicament ions for deliveryto the body. This effect is observed because the proton spongefunctional group traps the hydrogen ion (H⁺) via a scavenging reaction,rather than via ion-exchange.

The electrode of the present invention represents a milestone in thedevelopment of advanced iontophoresis systems. In addition to thebenefits of proton sponge incorporation into the inventive electrode,other important benefits exist. For example, one significant benefit ofthe electrode 10 is the ability to closely and accurately control thedosage of any pH buffering material that is included in the reservoir12. Incorporation of the pH buffering material into the reservoir 12secures the pH buffering material within the structure of the reservoir12 and prevents losses of pH buffering material from the reservoir 12during assembly, handling, and use of the electrode. Another significantbenefit of the electrode 10 is the ability to closely and accuratelycontrol the dosage of any proton sponge functional groups that areincluded in the reservoir 12. Incorporation of the proton sponge intothe reservoir 12 secures the proton sponge functional groups within thestructure of the reservoir 12 and prevents losses of proton spongefunctional groups from the reservoir 12 during assembly, handling, anduse of the electrode.

In practice, use of the iontophoresis system that includes the cathodeand/or the anode, that is structured like the electrode 10, is efficientand convenient. Where the active electrode of the iontophoresis systemis structured like the electrode 10, the electrolytic solution may beinjected into the reservoir 12 of the electrode 10 after formation ofthe electrode 10 using any conventional technique, such as with ahypodermic syringe. Medicament ions that will be delivered to the bodyare typically included in the electrolytic solution by dissociating theionic substance of interest in the appropriate solvent before theelectrolytic solution is injected into the reservoir 12. For electrodesthat will not be used to iontophoretically deliver medicament ions, theelectrolytic solution that includes the conductive ions may be injectedinto the reservoir 12 of the electrode 10 after formation of theelectrode 10 using any conventional technique, such as with thehypodermic syringe. Furthermore, as already explained, differentmedicament ions may be placed in the different electrolytic solutionsthat are placed in the cathode and the anode, for simultaneousiontophoretic delivery from both the cathode and the anode.

Next, both of the electrodes of the iontophoresis system are attached tothe surface of the body, such as the skin of the patient. For anyelectrode of the iontophoresis system that is structured like theelectrode 10, the reservoir 12 faces the skin, the terminal 16 facesaway from the skin, and the adhesive cover 20 is attached to the skin tosecure the electrode 10 to the body. If the ground electrode of theiontophoresis system is structured like the electrode 10, the terminal16 of the electrode 10 is comiected to the source of electrical power tosupport current flow through the body. If the active electrode of theiontophoresis system is structured like the electrode 10, the terminal16 of the electrode 10 is connected to the source of electrical power toinitiate delivery of medicament ions into the body.

It should also be understood that the anode and the cathode may also beconnected to the source of electrical power such that the iontophoresiselectrode that includes the anode structured like the electrode 10and/or the cathode structured like the electrode 10 is capable ofproviding suitable current flow to the body to stimulate a muscle of thebody. In this application, the electrode 10 may include eitherelectrolytic solution that includes medicament ions, if delivery ofmedicament ions will coincide with muscle stimulation. Alternatively,the electrode 10 may include electrolytic solution that is free ofmedicament ions and that includes conductive ions, if delivery ofmedicament ions will not coincide with muscle stimulation. In the caseof muscle stimulation alone, the current source would supply anappropriate current form, such as alternating current.

Although the present invention has been described with reference topreferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

What is claimed is:
 1. A pH buffered electrode comprising:a reservoirfor holding electrolytic solution, the reservoir comprising foam; a pHbuffer, the pH buffer chemically bonded to the foam; and; an electricalconnection in electrical communication with the reservoir.
 2. The pHbuffered electrode of claim 1 wherein the foam is selected from thegroup consisting of phenol-formaldehyde; polyurethane; polyethylene;polyvinyl alcohol; any copolymer of phenol-formaldehyde, polyurethane,polyethylene, and polyvinyl alcohol; and a mixture of any of these. 3.The pH buffered electrode of claim 1 wherein the pH buffer comprises ionexchange material.
 4. The pH buffered electrode of claim 1 wherein thepH buffer comprises a proton sponge or a functional group capable ofscavenging ions.
 5. The pH buffered electrode of claim 1, and furthercomprising carbonized particles, the carbonized particles dispersedwithin and immobilized within the reservoir, the carbonized particlescapable of making the reservoir conductive.
 6. The pH buffered electrodeof claim 1, the electrode further comprising electrolytic solution, thereservoir holding all, or substantially all, of the electrolyticsolution that is comained in the electrode.
 7. A use of the pH bufferedelectrode of claim 1, the use comprising:injecting electrolytic solutioninto the reservoir; locating the electrode against a surface of a bodywith the reservoir in working relation with the surface of the body; andconnecting the electrial connection to a source of electrical power. 8.A method of making a pH buffered electrode, the methodcomprising:chemically bonding a pH buffer to a foam; creating areservoir for holding electrolytic solution, the reservoir comprisingthe pH buffer and the foam; and placing an electrical connection inelectrical communication with the reservoir.
 9. The method of claim 8wherein the foam is selected from the group consisting ofphenol-formaldehyde; polyurethane; polyethylene; polyvinyl alcohol; anycopolymer of phenol-formaldehyde, polyurethane, polyethylene, andpolyvinyl alcohol; and a mixture of any of these.
 10. The method ofclaim 8 wherein the pH buffer comprises ion exchange material.
 11. Themethod of claim 8 wherein the pH buffer comprises a proton sponge or afunctional group capable of scavenging ions.
 12. The method of claim 8,the method further comprising dispersing and immobilizing carbonizedparticles within the reservoir, the carbonized particles capable ofmaking the reservoir conductive.
 13. The method of claim 8, the methodfurther comprising filling the reservoir with electrolytic solution, thereservoir holding all, or substantially all, of the electrolyticsolution that is contained in the electrode.
 14. A pH buffered electrodemade by the method of claim
 8. 15. The use of a pH buffered electrodemade by the method of claim 8, the use comprising:injecting electrolyticsolution into the reservoir; locating the electrode agamnst a surface ofa body with the reservoir in working relation with the surface of thebody; and connecting the electrical connection to a source of electricalpower.